Psychostimulant (methamphetamine [METH] and cocaine) abuse has reached an epidemic proportion in the US and worldwide, presenting profound socioeconomic, legal and medical problems. In addition, it is a significant comorbid factor for other psychiatric disorders, e.g., schizophrenia, bipolar disorder, and adversely affects their clinical courses and treatment responses. Unfortunately, no monotherapeutic treatments tested in double-blind clinical trials have shown consistent efficacy in maintaining long-term abstinence. In contrast to this unmet clinical need for effective therapeutic strategies, our preclinical projects have consistently demonstrated that a combination of dopamine a clinically-available (DA) agonist and the antiemetic ondansetron (Zofran(R)) can reverse behavioral and neurobiological alterations observed in animal models of psychostimulant abuse. A timely laboratory-to-clinics translation of our remarkable efficacy results has been hampered by a lack of practical means to ensure the required regimen compliance (two drugs, 3.5 h apart). This shortcoming is especially problematic for psychostimulant abusers, who are typically unwilling or unable to observe prescribed treatment plans. In partnerships with commercial formulation companies, we intend to overcome this translational hurdle by developing novel pulsatile-release ondansetron formulations (Ond-PR) that will undergo delayed absorption in the gastrointestinal tract. These formulations will be tested in three sequential studies: (1) Ond-PR pharmacokinetic characterization;(2) determination of pharmacokinetic, safety and pharmacodynamic interactions with simultaneously-administered immediate-release methylphenidate;(3) a proof-of-concept phase II efficacy trial on a combination of immediate-release methylphenidate and Ond-PR. The present project directly addresses one of the NIDA's high priority topics, namely "Small Molecule Development for Substance Related Disorders." The stated goal of this topic is to "develop safe and effective medications for the treatment of drug addictions." With respect to the goals of the Recovery Act, this project will provide necessary resources for accelerated laboratory- to-clinics translation of novel treatment strategy against psychostimulant abuse. PUBLIC HEALTH RELEVANCE: Methamphetamine and other psychostimulant (cocaine) abuse continue to impose unacceptable legal, socioeconomic and medical costs worldwide. In spite of much effort, no treatment has been shown to be effective in treating psychostimulant abuse. We are proposing to develop novel formulations of clinically-available anti-emetic drug ondansetron to allow rapid laboratory-to-clinics translation of our combination treatment regimen that has shown consistent and robust efficacy in animal models of psychostimulant abuse.